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US 8,785,436 B2Granted
1,3-oxazines as BACE 1 and/or BACE2 inhibitors
AssigneeHoffmann-La Roche Inc.
InventorsHans Hilpert, Robert Narquizian, Emmanuel Pinard, Alessandra Polara, Mark Rogers-Evans, Thomas Woltering, Wolfgang Wostl
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Abstract
The present invention provides compounds of formula I having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease and type 2 diabetes.
Claims27
A compound of formula I,
- wherein
- X is selected from the group consisting of
- aryl,
- aryl substituted by 1-2 substituents individually selected from R1,
- heteroaryl,
- heteroaryl substituted by 1-2 substituents individually selected from R1 and halogen-aryl,
- C3-6-cycloalkyl, and
- C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R1;
- Y is selected from the group consisting of
- —C═O—NH—,
- —CH2—,
- —NH—
- —NH—CHR7—,
- —O—CH2—, and
- absent;
- Z is selected from the group consisting of
- aryl,
- aryl substituted by 1-2 substituents individually selected from R8,
- heteroaryl,
- heteroaryl substituted by 1-2 substituents individually selected from R8,
- C3-6-cycloalkyl,
- C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R8,
- heterocyclyl,
- heterocyclyl substituted by 1-2 substituents individually selected from R8,
- C2-6-alkynyl,
- C1-6-alkyl, and
- C1-6-alkyl substituted by 1-3 substituents individually selected from R9;
- R1 is selected from the group consisting of
- hydrogen,
- halogen, and
- C1-6-alkyl;
- R2 is selected from the group consisting of
- hydrogen,
- C1-6-alkyl, and
- halogen-C1-3-alkyl;
- R3 is selected from the group consisting of
- hydrogen,
- halogen, and
- C1-6-alkyl;
- R4 is selected from the group consisting of
- hydrogen
- halogen, and
- C1-6-alkyl;
- R5 is selected from the group consisting of
- hydrogen and
- C1-6-alkyl;
- R6 is selected from the group consisting of
- hydrogen and
- C1-6-alkyl;
- R7 is selected from the group consisting of
- hydrogen and
- C1-6-alkyl;
- R8 is selected from the group consisting of
- halogen,
- cyano,
- C1-6-alkyl,
- halogen-C1-6-alkyl,
- C1-6-alkoxy,
- halogen-C1-6-alkoxy,
- aryl,
- halogen-aryl, and
- C3-6-cycloalkyl;
- and
- R9 is selected from the group consisting of
- halogen,
- cyano,
- C1-6-alkoxy, and
- halogen-C1-6-alkoxy;
- or a pharmaceutically acceptable salt thereof.
66 more elements
A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
- wherein
- X is selected from the group consisting of
- aryl,
- aryl substituted by 1-2 substituents individually selected from R1,
- heteroaryl,
- heteroaryl substituted by 1-2 substituents individually selected from R1 and halogen-aryl,
- C3-6-cycloalkyl, and
- C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R1;
- Y is selected from the group consisting of
- —C═O—NH—,
- —CH2—,
- —NH—
- —NH—CHR7—,
- —O—CH2—, and
- absent;
- Z is selected from the group consisting of
- aryl,
- aryl substituted by 1-2 substituents individually selected from R8,
- heteroaryl,
- heteroaryl substituted by 1-2 substituents individually selected from R8,
- C3-6-cycloalkyl,
- C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R8,
- heterocyclyl,
- heterocyclyl substituted by 1-2 substituents individually selected from R8,
- C2-6-alkynyl,
- C1-6-alkyl, and
- C1-6-alkyl substituted by 1-3 substituents individually selected from R9;
- R1 is selected from the group consisting of
- hydrogen,
- halogen, and
- C1-6-alkyl;
- R2 is selected from the group consisting of
- hydrogen,
- C1-6-alkyl, and
- halogen-C1-3-alkyl;
- R3 is selected from the group consisting of
- hydrogen,
- halogen, and
- C1-6-alkyl;
- R4 is selected from the group consisting of
- hydrogen
- halogen, and
- C1-6-alkyl;
- R5 is selected from the group consisting of
- hydrogen and
- C1-6-alkyl;
- R6 is selected from the group consisting of
- hydrogen and
- C1-6-alkyl;
- R7 is selected from the group consisting of
- hydrogen and
- C1-6-alkyl;
- R8 is selected from the group consisting of
- halogen,
- cyano,
- C1-6-alkyl,
- halogen-C1-6-alkyl,
- C1-6-alkoxy,
- halogen-C1-6-alkoxy,
- aryl,
- halogen-aryl, and
- C3-6-cycloalkyl;
- and
- R9 is selected from the group consisting of
- halogen,
- cyano,
- C1-6-alkoxy, and
- halogen-C1-6-alkoxy;
- or a pharmaceutically acceptable salt thereof
- and a pharmaceutically acceptable carrier.
67 more elements
Dependencies are inferred from the claim text.